Journal of Gastroenterology

, Volume 46, Issue 2, pp 129–137 | Cite as

The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease

  • Makoto Naganuma
  • Toshimitsu Fujii
  • Mamoru Watanabe
Review

Abstract

Background

Intravenous cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory ulcerative colitis (UC). Like the response to CsA, clinical trials have shown that two-thirds of patients with refractory UC respond to tacrolimus therapy. However, it is unclear how/when this agent should be used for patients with active UC.

Methods

We reviewed the results of previous studies regarding calcineurin inhibitors in UC patients. We examined the best way to use tacrolimus to obtain maximum efficacy by comparing the results from clinical trials with those from a recent survey in Japan.

Results

Calcineurin inhibitors are useful to induce remission in patients with refractory UC; however, the long-term prognosis has not been shown to be improved by CsA. Early intervention with CsA/tacrolimus may improve the long-term prognosis of UC patients just as infliximab does for Crohn’s disease patients. Recent studies have indicated that a fasting state and administration of a higher dosage of tacrolimus at the beginning of therapy are critical in ensuring that the target trough concentration of the agent is reached.

Conclusions

The use of higher initial doses of tacrolimus ensured that patients achieved their target levels. Further studies will be needed to elucidate the efficacy of top-down therapy with tacrolimus in patients with UC. Physicians must know how to use calcineurin inhibitors to obtain maximum efficacy.

Keywords

Cyclosporine A Tacrolimus Infliximab Refractory ulcerative colitis 

References

  1. 1.
    Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. Br Med J. 1955;2:104–8.CrossRefGoogle Scholar
  2. 2.
    Baron JH, Connell AM, Kanaghinis TG, Lennard-Jones JE, Jones AF. Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Br Med J. 1962;2:441–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories. Gut. 2006;55:437–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Hanai H, Watanabe F, Takeuchi K, Iida T, Yamada M, Iwaoka Y, et al. Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study. Clin Gastroenterol Hepatol. 2003;1:28–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Hanai H, Watanabe F, Yamada M, Sato Y, Takeuchi K, Iida T, et al. Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis. Digestion. 2004;70:36–44.CrossRefPubMedGoogle Scholar
  6. 6.
    Naganuma M, Funakoshi S, Sakuraba A, Takagi H, Inoue N, Ogata H, et al. Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitis. Inflamm Bowel Dis. 2004;10:251–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Sawada K, Kusugami K, Suzuki Y, Bamba T, Munakata A, Hibi T, et al. Leukocytapheresis in ulcerative colitis: results of a multicenter double-blind prospective case–control study with sham apheresis as placebo treatment. Am J Gastroenterol. 2005;100:1362–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Emmrich J, Petermann S, Nowak D, Beutner I, Brock P, Klingel R, et al. Leukocytapheresis (LCAP) in the management of chronic active ulcerative colitis—results of a randomized pilot trial. Dig Dis Sci. 2007;52:2044–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Sands BE, Sandborn WJ, Feagan B, Löfberg R, Hibi T, Wang T, et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology. 2008;135:400–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Abraham C, Cho JH. Inflammatory bowel disease. New Engl J Med. 2009;361:2066–78.CrossRefPubMedGoogle Scholar
  11. 11.
    Abbas AK, Lichtman AH. Activation of T lymphocytes. In: Malley J, editor. Cellular and molecular immunology. 5th ed. Philadelphia: Saunders; 2003.Google Scholar
  12. 12.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–4.CrossRefPubMedGoogle Scholar
  13. 13.
    McGeachy MJ, Cua DJ. The link between IL-23 and Th17 cell-mediated immune pathologies. Semin Immunol. 2007;19:372–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet. 1990;336:16–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–5.CrossRefPubMedGoogle Scholar
  16. 16.
    D’Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, et al. Intravenous cyclosporin versus intravenous glucocorticosteroids as a single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001;120:1323–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Van Assche G, D’Haens G, Noman M, Vermeire S, Hiele M, Asnong K, et al. Randomized double-blind comparison of 4 mg/kg/day versus 2 mg/kg/day intravenous cyclosporin in severe ulcerative colitis. Gastroenterology. 2003;125:1025–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Moskovitz D, Van Assche G, Maenhout B, Arts J, Ferrante M, Vermeire S, et al. Incidence of colectomy during long term follow up after cyclosporin-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:760–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol. 2005;17:79–84.CrossRefPubMedGoogle Scholar
  20. 20.
    Arts J, D’Haens G, Zeegers M, Van Assche G, Hiele M, D’Hoore A, et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis. 2004;10:73–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Message L, Bourreille A, Laharie D, Quinton A, Galmiche JP, Lamouliatte H, et al. Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids. Gastroenterol Clin Biol. 2005;29:231–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Fernandez-Banares F, Bertran X, Esteve-Comas M, Cabre E, Menacho M, Humbert P, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol. 1996;91:2498–9.PubMedGoogle Scholar
  23. 23.
    Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94:1587–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Kobayashi T, Naganuma M, Okamoto, Hisamatsu T, Inoue N, Ichikawa H, et al. 2010. Rapid endoscopic improvement is important for 1-year avoidance of colectomy but not for the long-term prognosis in cyclosporine A treatment for ulcerative colitis. J Gastroenterol (in press).Google Scholar
  25. 25.
    Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–87.CrossRefPubMedGoogle Scholar
  26. 26.
    Naganuma M, Ichikawa H, Inoue N, Kobayashi T, Okamoto S, Hisamatsu T, et al. Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients. J Gastroenterol. 2010;45:936–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Asshue GV, Vermeire S, Rutgeerts P. Treatment of severe steroid refractory ulcerative colitis. World J Gastroenterol. 2008;14:5508–11.CrossRefGoogle Scholar
  28. 28.
    Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMedGoogle Scholar
  29. 29.
    Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Carter M, Lobo AJ, Travis SPL. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53(Suppl V):1–16.CrossRefGoogle Scholar
  31. 31.
    Järnerot G, Hertervig E, Friis-liby I, Blomquist L, Karlén P, Grännö C, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized placebo-controlled study. Gastroenterology. 2005;128:1805–11.CrossRefPubMedGoogle Scholar
  32. 32.
    Fellermann K, Tanko Z, Herrlinger KR, Witthoeft T, Homann N, Bruening A, et al. Response of refractory colitis to intravenous or oral tacrolimus (FK506). Inflamm Bowel Dis. 2002;8:317–24.Google Scholar
  33. 33.
    Hogenauer C, Wenzl HH, Hinterleitner TA, Petritsch W. Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Aliment Pharmacol Ther. 2003;18:415–23.CrossRefPubMedGoogle Scholar
  34. 34.
    Ogata H, Matsui T, Nakamura M, Iida M, Takazoe M, Suzuki Y, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255–62.CrossRefPubMedGoogle Scholar
  35. 35.
    Baumgart DC, Macdonald JK, Feagan B. Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis. Cochrane Database Syst Rev. 2008;3:CD007216.PubMedGoogle Scholar
  36. 36.
    Romano C, Comito D, Famiani A, Fries W. Oral tacrolimus (FK 506) in refractory paediatric ulcerative colitis. Aliment Pharmacol Ther. 2010;31:676–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Yamamoto S, Nakase H, Mikami S, Inoue S, Yoshino T, Takeda Y, et al. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis. Aliment Pharmacol Ther. 2008;28:589–97.CrossRefPubMedGoogle Scholar
  38. 38.
    Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease—a long-term follow-up. Am J Gastroenterol. 2006;101:1048–56.CrossRefPubMedGoogle Scholar
  39. 39.
    Ng SC, Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:129–34.CrossRefPubMedGoogle Scholar
  40. 40.
    Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis. 2008;14:7–12.CrossRefPubMedGoogle Scholar
  41. 41.
    Baumgart DC, Wiedenmann B, Dignass AU. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther. 2003;17:1273–81.CrossRefPubMedGoogle Scholar
  42. 42.
    D’Haens G. Infliximab for ulcerative colitis: finally some answers. Gastroenterology. 2005;128:2161–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Herrlinger KR, Barthel DN, Schmidt KJ, Büning J, Barthel CS, Wehkamp J, et al. Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther. 2010;31:676–7.CrossRefGoogle Scholar
  44. 44.
    Yamamoto S, Nakase H, Matsuura M, Honzawa Y, Masuda S, Inui K, et al. Efficacy and safety of infliximab as rescue therapy for ulcerative colitis refractory to tacrolimus. J Gastroenterol Hepatol. 2010;25:886–91.CrossRefPubMedGoogle Scholar
  45. 45.
    Maser EA, Deconda D, Lichtiger S, Ullman T, Present DH, Kornbluth A. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol. 2008;6:1112–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Ng SC, Kamm MA. Therapeutic strategies for the management of ulcerative colitis. Inflamm Bowel Dis. 2009;15:935–50.CrossRefPubMedGoogle Scholar
  47. 47.
    Travis SP, Stange EF, Lémann M, Oresland T, Chowers Y, Forbes A, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut. 2006;55(Suppl 1):i16–35.CrossRefPubMedGoogle Scholar
  48. 48.
    D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Baert F, Moortgat L, Van Assche G, Caenepeel P, Vergauwe P, De Vos M, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Lichtiger S. Treatment of choice for acute severe steroid-refractory ulcerative colitis is cyclosporine. Inflamm Bowel Dis. 2009;15:141–2.CrossRefPubMedGoogle Scholar
  51. 51.
    Sakuraba A, Sato T, Naganuma M, Morohoshi Y, Matsuoka K, Inoue N, et al. A pilot open-labeled prospective randomized study between weekly and intensive treatment of granulocyte and monocyte adsorption apheresis for active ulcerative colitis. J Gastroenterol. 2008;43:51–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Sakuraba A, Motoya S, Watanabe K, Nishishita M, Kanke K, Matsui T, et al. An open-label prospective randomized multicenter study shows very rapid remission of ulcerative colitis by intensive granulocyte and monocyte adsorptive apheresis as compared with routine weekly treatment. Am J Gastroenterol. 2009;104:2990–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Fukunaga K, Yokoyama Y, Kamikozuru K, Hida N, Ohda Y, Nakamura S, et al. A prospective randomized double blind sham controlled trial to assess the efficacy of monthly granulocyte/monocyte adsorption apheresis as maintenance therapy for patients with steroid refractory ulcerative colitis. Gut. 2010;59:A73.Google Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Makoto Naganuma
    • 1
  • Toshimitsu Fujii
    • 1
  • Mamoru Watanabe
    • 1
  1. 1.Department of Gastroenterology, School of MedicineTokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations